4 M. M.W.
Ulrich
1.1 Background
1 position and architecture of the extracellular matrix,
Wound healing is a complex and tightly regulated pro-
cess and can be divided in three different overlapping
phases: the inflammatory phase, the proliferation phase,
and the remodeling phase. The first phase begins directly
after wounding and is characterized by hemostasis and
inflammation. Platelets play an important role in the
formation of the blood clot to stop the bleeding, and
through the secretion of chemokines, they recruit differ-
ent inflammatory cells such as neutrophils and mono-
cytes to the wound. The inflammatory cells clean the
wound by phagocytosis of invading microorganisms
and damaged tissue. The inflammatory cells also secrete
chemotactic signals which attract fibroblasts and endo-
thelial cells to the wound which, together with the
inflammatory cells, form the granulation tissue. This is
the proliferation phase during which the destroyed tis-
sue is replaced. During this phase, the keratinocytes
migrate over the granulation tissue to form a new epi-
dermis to close the skin defect.
The last phase in wound healing is the remodeling
phase which is characterized by a decrease in cellularity
and vascularity by apoptosis and an increase of synthesis
and deposition of the components of the extracellular
matrix (ECM). In adults, this process results is scar for-
mation, whereas in fetal skin, complete regeneration of
the skin, including the formation of skin appendices such
as hairs and sebaceous and sweat glands, takes place.
Since the 1950, studies on scarless healing in fetal
skin in animals have been published, and in the late
1970s of the last century, the first publications appeared
describing scarless healing of fetal skin wounds in
humans. Since then, several experimental studies on this
subject have been published. From experimental animal
and human studies it is known that scarless healing only
occurs during the first period of gestation. Human
fetuses lose the ability of skin regeneration around
22 weeks of gestation.
Animal experiments in which adult, late gestational,
and early gestational fetal skin were transplanted on
early gestational fetuses showed clear differences in
wound healing outcome. Incision wounds created in
these transplants showed scar formation in adult and
late gestational fetal skin, whereas the wound created in
the fetal skin resulted in complete regeneration [1].
These experiments show not only that this phenomenon
is an intrinsic property of the fetal skin itself but also
that scarless healing is not triggered by the intrauterine
environment. Interestingly, the wounds at the fetal-adult
interface also healed without scar formation implicating
that direct contact of a wound with fetal skin is suffi-
cient to induce regeneration of the tissue [2].
Several mechanisms have been suggested to be
responsible for the scarless healing in fetal skin, e.g., a
diminished inflammatory reaction, differences in com-
and mechanical load in fetal skin. Furthermore, fetal
skin differs from adult skin in many factors commonly
associated with scar formation such as proteolytic activ-
ity and TGF-β secretion and sensitivity. This chapter
will discuss the different mechanisms during the three
phases of wound healing proposed in the literature to be
involved in scarless healing.
1.2 Inflammation
Several studies have shown that the inflammatory
response to injury is strongly reduced in fetal skin
wounds, and induction of the local inflammation causes
scar formation in early fetal skin.
The inflammatory reaction involves recruitment of
inflammatory cells which produce inflammatory media-
tors such as growth factors and cytokines. The growth
factors and cytokines subsequently recruit more inflam-
matory cells.
Inflammation in adult wound healing starts off with
a pro-inflammatory cytokine and immune cell response
and the activation of the acute phase response. During
this period, invading microorganisms and injured tissue
are cleared from the wound bed. Subsequently, the
inflammatory reaction is skewed to an anti-­inflammatory
profile which initiates the healing response. Although
the exact role of inflammatory cells in scar formation is
not entirely elucidated, it is evident that they play an
important role in the derailed wound healing process
leading to scar formation. It was shown that in severely
scarred wounds such as burn wounds, the acute (pro-)
inflammatory status is continued for a very long time.
Cells involved in the pro-inflammatory reaction are
neutrophils and the M1 subtype macrophages, while
macrophages of the M2 subtypes and regulatory T cells
are anti-inflammatory, pro-healing cells.
Platelets are the first cells involved in the induction of
the inflammatory reaction. The platelets are activated
and aggregate during the coagulation phase forming the
hemostatic plug. The activated platelets release cyto-
kines such as platelet-derived growth factor (PDGF),
interleukins (IL) 1 and 6, and transforming growth fac-
tor beta (TGF-β) into the wound environment. It was
shown that fetal platelets aggregate poorly when exposed
to higher levels of hyaluronic acid, a component of the
extracellular matrix, which is more abundantly expressed
in fetal skin than in adult skin, and subsequently release
lower levels of platelet-derived cytokines.
The lower platelet-derived cytokines are most likely
responsible for the reduced inflammatory cell infiltra-
tion, such as neutrophils, macrophages, and lympho-
cytes, seen in fetal wounds at early gestational age [3].